doi: 10.1161/01.CIR.0000129507.12719.80
(Circulation. 2004;109:II-11 – II-14.)
© 2004 American Heart Association, Inc.
Vascular Effects of Statins |
CRP as a Mediator of Disease
From the Research Center for Cardiovascular Diseases, University of Texas-Houston Health Science Center, and the Department of Cardiology, University of Texas-MD Anderson Cancer Center, Houston, Tex.
Correspondence to Edward T.H. Yeh, MD, Department of Cardiology, University of Texas-MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 449, Houston, TX 77030. E-mail etyeh{at}mdanderson.org
Abstract
Of the various hypotheses offered to explain atherosclerosis, inflammation now appears to provide a key to this pathological process. Inflammation has been shown to play a major role in precipitating a cascade of events from formation of the atheromatous lesion in response to vascular injury through lipid ingestion by macrophages, to subsequent rupture of the lesion, and myocardial infarction. Atherosclerosis shares many inflammatory features with rheumatoid arthritis (RA), an autoimmune disease, and drugs that block the inflammatory cytokine pathway now provide effective treatment for RA. In animal models, blockers of the inflammatory cytokine pathway appear to block mononuclear cell binding to arterial plaque. C-reactive protein (CRP), an inflammatory marker, may also play a proinflammatory role in activating monocyte chemotactic protein. Antiatherosclerotic drugs may be exerting some of their beneficial effects by inhibiting the harmful effects of CRP.
Key Words: atherosclerosis • C-reactive protein • cytokine pathway • inflammation • monocyte
Accumulating evidence suggests that inflammation plays a significant role in the development and progression of coronary artery disease. This was not always the case, however. Over 100 years ago, Dr. William Osler stated in his Principle and Practice of Medicine that, "longevity is a vascular question. A man is only as old as his arteries." At that time, atherosclerosis was considered to be a process of aging: as the artery ages, it hardens. The aging hypothesis was supplanted by the lipid hypothesis, which states that genetics and a high cholesterol diet ultimately lead to the development of fatty streaks, the earliest lesion of atherosclerosis. With the discovery of growth factors and their receptors, the response-to-injury hypothesis was proposed to explain the fibroproliferative response of the vessel wall to the initial lipid damage. More recently, the inflammation hypothesis has taken hold, tying together the lipid hypothesis and the response-to-injury hypothesis with a new level of sophistication.
According to the inflammation hypothesis, local inflammatory stimuli, such as oxidized low-density lipoprotein (LDL), an advanced glycation end product from diabetes, or an infectious process, can change the milieu of the arterial wall and prompt production of a number of adhesion molecules and chemokines.1 Thus, circulating mononuclear cells would be initially slowed down by interaction with the selectins expressed on the endothelial cells. Subsequently, recruitment and activation of the mononuclear cells occur via activation of chemokine receptors; this in turn leads to firm adhesion of the mononuclear cells through interaction of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) and their counter-receptors (Figure 1). Finally, the monocytes transmigrate through the endothelial cell junction to enter the inflamed arterial wall. The initial entry of the mononuclear cells sets the stage for the early lesion, or fatty streak. Tissue macrophages ingest lipids and become foam cells, which become apoptotic, turning into a necrotic lipid core. At the same time, smooth muscle cells are recruited to the intima to participate in the repair process; they begin to form a protective cap over the necrotic material. T-cells recruited to the intima produce cytokines that serve to thin this fibrous cap. In situations in which the repair is incomplete or the environment is too hostile, the lesion can rupture and initiate clot formation, leading to complete occlusion of the vascular lumen and heart attack.
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The study of atherosclerosis has been greatly facilitated by the availability of animal models, in particular, models in which hyperlipidemias are genetically manipulated. For example, the apoE-deficient mouse is an excellent model that mimics human disease closely, not only in the cellular composition of plaques but also in their location. Our laboratory has developed an in vivo model of monocyte recruitment using the apoE-deficient mouse; mononuclear cells are labeled with fluorescent beads and injected intravenously.2 The injected cells have been observed in the liver, lung, kidney, and spleen. Interestingly, the mononuclear cells have been found to reside in the macrophage area of the spleen but not in the T- and B-cell areas, demonstrating specificity of the homing process. Most importantly, we can quantitate the number of mononuclear cells that adhere to the proximal 1-mm surface of the endothelial cell lining of the aortic sinus and ascending aorta. We have also shown that preinjection of antibodies against ICAM-1 or 
4ß1, but not E-selectin, can inhibit the binding of the mononuclear cells to the plaque. Thus, the binding appears to be specific.
Inflammatory processes in atherosclerosis resemble those in rheumatoid arthritis (RA), an autoimmune disease (Table). In an editorial entitled "A Tale of Two Diseases—Atherosclerosis and Rheumatoid Arthritis," atherosclerosis and RA were compared according to inflammatory parameters.3 Both disease processes involve monocyte activation, T- and B-cell activation, endothelial cell activation, and elevation of C-reactive proteins (CRP). Using the apoE-deficient mouse model, we showed that blockers of the inflammatory cytokine pathway, such as interleukin (IL)-1 RA and tumor necrosis factor (TNF)-receptor antagonist, block mononuclear-cell binding to the plaque (E. T. H. Yeh, MD and J. T. Willerson, MD, unpublished data, July 2003). It should be noted that TNF-receptor blockade is now the treatment of choice for RA.
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CRP is an acute phase reactant that was discovered over 70 years ago to be a blood protein that binds to the C-polysaccharide of pneumococci. CRP is a pentamer of 23 kDa subunits; its level is usually low in normal individuals but can rise 100- to 200-fold or higher with acute systemic inflammation.4 Cardiologists have measured CRP and other inflammatory markers in various clinical settings and have shown that CRP levels are high in patients with acute coronary syndrome and can be used to predict outcome in those patients.5 Most interestingly, levels of CRP predict future cardiovascular (CV) risk in apparently healthy men and women. Ridker et al6 first reported that CRP level predicts future myocardial infarction and stroke. Subsequent studies have been expanded to include additional CV complications, including peripheral vascular disease. Combining measurements of the cholesterol level with the CRP level enhances the predictive value of CRP (Figure 2).7 When both CRP and cholesterol levels are high, a person’s overall risk of developing a CV event increases up to 9-fold compared with that of a person with low CRP and cholesterol levels.8
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Why is CRP such a good predictor of future CV events? CRP could simply be a marker of inflammation that reflects the inflammatory load of the body. Thus, any inflammatory stimuli would prompt the release of IL-1, IL-6, and TNF, which can stimulate the liver to produce CRP. Alternatively, CRP could have a more direct proinflammatory role. Using cultured human umbilical vein endothelial cells as a model, we showed that CRP activates endothelial cells to express ICAM-1 in a manner comparable to that observed with stimulation with IL-1ß.9 CRP can induce endothelial cells to produce VCAM-1 and E-selectin, too, but not platelet and endothelial cell adhesion molecule-1. We also showed dose-dependent induction of adhesion molecules. Furthermore, we showed that cultured human coronary artery endothelial cells respond to CRP in a manner analogous to that of human umbilical vein endothelial cells. These facts considered together suggest that CRP has a profound proinflammatory property, and the proinflammatory effect is observed at CRP levels frequently seen in patients. CRP can also activate the production of monocyte chemotactic protein-1 (MCP-1).10 Thus, CRP can activate the entire recruitment cascade. Using MCP-1 activation as an assay, we showed that both statins and fenofibrates can inhibit CRP-induced MCP-1 induction, whereas acetylsalicyclic acid cannot. Thus, some of the antiatherosclerotic drugs may exert their effects through the CRP axis (Figure 3).
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Finally, looking at the way we have treated atherosclerosis over the years, we can see that inflammation has already been targeted, via acetylsalicyclic acid and statin therapies. Risk-factor modifications, such as weight reduction and smoking cessation, may also reduce CRP levels. However, CRP-guided antiinflammatory therapy may now take center stage in our fight against atherosclerosis.
References
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